Objective To analyze the differences with the expression of glucocorticoids receptor isoforms ( GRα, GRβ, GRγand GR-P ) and cytokines [ IL-6, macrophage migration inhibitory factor (MIF), IFN-γand IL-10] between patients with systemic lupus erythematosus (SLE) and rheumatoid ar-thritis ( RA) , and to further understand their correlations with disease activities.Methods Fifty-five pa-tients with SLE, forty-nine patients with RA and thirty-eight healthy subjects were recruited in this study. All patients were steroid-naive.The expression of GRα, GRβ, GRγ, and GR-P in peripheral blood mononu-clear cells at transcript levels were determined by real-time PCR.Enzyme-linked immunosorbent assay was used to detect the expression of IL-6, MIF, IFN-γand IL-10 in serum samples.Results The percentages of GRαin all subjects were the highest among four isoforms of GR, followed by GR-P, GRγand GRβ.Com-pared with healthy subjects, patients with SLE or RA showed significantly decreased expression of GRα( P<0.05), but increased expression of GR-P (P<0.05).The percentages of GR-P in patients with RA were higher than those in patients with SLE (P<0.05).The expression of GRαwas negatively correlated with SLE disease activity index (SLEDAI) and disease activity score 28 (DAS28).SLE or RA patients with high disease activity showed lower expression of GRαthan those with low disease activity.The levels of IL-6, IFN-γand MIF in patients with SLE or RA were significantly higher than those in healthy subjects ( P<0.05).A negative correlation was observed between the expression of IL-6 and GRαin patients with SLE (P<0.05).The expression of IFN-γwas negatively correlated with GRαin patients with RA (P<0.05). Conclusion There were significant differences with the expression of GR isoforms among patients with SLE, patients with RA and healthy subjects, indicating the change of internal environment in patients might be in-volved in GR alternative splicing.GRαwas the predominant isoform and was negatively correlated with dis-ease activities.Oversecretion of cytokines resulted in a decreased expression of GRα.This study would be useful for the diagnosis of the disease status and for monitoring clinical treatment.

Objective To investigate the mRNA level of glucocorticoid receptor α (GRα) and heat shock protein 90 (HSP90) in peripheral blood mononuclear cells (PBMCs) and the plasma protein level of macrophage migration inhibitory factor (MIF) in patients with systemic lupus erythematosus (SLE) and to analyze their association with glucocorticoid (GC) resistance.Methods One hundred and six patients with SLE and thirty-eight healthy controls were enrolled in this study.Transcription levels of GRα and HSP90 were determined by real-time polymerase chain reaction.Enzyme-linked immunosorbent assay was used to detect the protein level of plasma MIF.The association between these parameters and GC resistance was analyzed by Spearman correlation analysis.The multivariate logistic regression model was used to analyze the risk factors for GC resistance.Results The mRNA level of GRα and HSP90 in GC resistance group was significantly lower than that in GC sensitive group [10.18(3.12,17.20) vs 16.83(12.01,24.18), P =0.001;18.46(14.77,26.45) vs 25.84 (17.97,35.90), P =0.005].MIF protein level in GC resistance group was significantly higher than that in GC sensitive group [(23.21 ±7.98) μg/L vs (18.34 ±6.29)μg/L;P =0.013].The mRNA level of HSP90 in the high MIF group was significantly lower than that in the low MIF group [23.67 (13.84,28.32) vs 26.64 (23.61,47.16);P =0.001], as well as HSP90/GRαratio(P =0.008).Additionally, the plasma protein level of MIF was negatively correlated with HSP90 (r =-0.275, P =0.004) and HSP90/GRα ratio(r =-0.341, P ＜ 0.001).SLE activity index score in GC resistance group was significantly higher than that in GC sensitive group [(12.23 ±2.86) μg./L vs (9.63 ± 3.48) μg/L;P =0.003].Logistic regression model indicated that disease activity was an independent risk factor for GC resistance (OR =17.481, 95％ CI 1.747-174.903, P =0.015).Conclusions Our preliminary findings suggest that low mRNA level of GRα and HSP90 and high protein level of MIF are associated with GC resistance.Elevated MIF level in SLE patients may play an important role in the development of GC resistance through down-regulating HSP90 and destabilizing the balance of HSP90/ Grα.Disease activity is the risk factor for GC resistance, which might be the viable evidence of therapy response.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease. A cardinal histopathologic feature of HD is the progressive loss of striatal medium spiny neurons. As there is no effective treatment for this fatal disease so far, we explore the therapeutic potential of nortriptyline to identify drugs that might be effective treatments for HD. N548mu [ 1955-128] huntingtin stable ST14A cell line was cultured and incubated in the presence or absence of serial concentrations of nortriptyline. Then R6/2 transgenic HD mice were treated with nortriptyline from five to twenty-one weeks of age. Nortriptyline protected striatal cells expressing mutant huntingtin when shifted to a nonpermissive temperature. Nortriptyline delay the disease onset to 127 d in R6/2 mice as compared with 102 d in saline-treated controls, but nortriptyline did not significantly delay mortality. As a gross marker of lack of systemic toxicity, there was no significant difference in the weight of the treated and control R6/2 mice. The results demonstrate that clinically reasonable doses of one of the identified drugs, nortriptyline, delays disease onset in a mouse model of the disease more than any previously identified compound. The most desirable features of a drug for HD are minimal toxicity and the ability to extend symptom-free living. Nortriptyline appears to be one such good candidate.

Objective:To analyze clinical outcomes of myocardial incision and tearing for the treatment of myocardial bridge.Methods:A retrospective cohort study was conduct to review the clinical date of 29 patients who underwent surgical myotomy from January 2014 to January 2018 in the Second Hospital of Lanzhou University. A total of 11 patients(incision group) were experienced traditional myotomy on myocardial bridge that the myocardium was longitudinally incised along the direction of the coronary artery, while 18 patients(tearing group) were treated by myocardial incision combined with tearing that longitudinally incised myocardium and deeply tissue tearing. The operation time of surgical myotomy, the amount of bleeding, the number of branches of vascular injury and the number of ventricular ruptures during operation were compared between the two groups. After followed up half a year to one year, the clinical symptoms of angina pectoris, myocardial ischemia by electrocardiogram suggested, and coronary stenosis by coronary CT suggested were collected.Results:The operation time of surgical myotomy, the amount of bleeding patients and the number of branches of vascular injury during operation in the incision group were higher than those in the tearing group( P<0.05). There was no significant difference for the number of ventricular ruptures during operation( P>0.05). After followed up half a year to one year, there was no significant difference in the clinical symptoms of angina pectoris, myocardial ischemia by electrocardiogram suggested, and coronary stenosis by coronary CT suggested( P>0.05). Conclusion:Myocardial incision combined with tearing is a surgical procedure with short operation time and low bleeding risk, which is more beneficial than the traditional longitudinally incised for the myocardial bridge.

Inherited retinal diseases (IRDs), including retinitis pigmentosa, Usher syndrome, Cone-Rod degenerations, inherited macular dystrophy, Leber's congenital amaurosis, Leber's hereditary optic neuropathy are the most common and severe types of hereditary ocular diseases. So far more than 200 pathogenic genes have been identified. With the growing knowledge of the genetics and mechanisms of IRDs, a number of gene therapeutic strategies have been developed in the laboratory or even entered clinical trials. Here the progress of IRD research on the pathogenic genes and therapeutic strategies, particularly gene therapy, are reviewed.
Biomedical Research ; methods ; trends ; Clinical Trials as Topic ; Genetic Predisposition to Disease ; genetics ; Genetic Therapy ; methods ; trends ; Humans ; Mutation ; Retinal Diseases ; genetics ; therapy ; Treatment Outcome

OBJECTIVETo investigate the role of MT-ND1 m.3635G>A mutation in the pathogenesis of Leber's hereditary optic neuropathy (LHON).

METHODSBiochemical characteristics including the activity of complex Ⅰ, ATP production and oxygen consumption rate among lymphoblastoid cell lines derived from 3 carriers, 3 affected matrilineal relatives of the families and 3 controls were compared.

RESULTSComparison of mitochondrial functions in lymphoblastoid cell lines of the carriers, patients and controls showed a 51.0% decrease in the activity of complex Ⅰ in patients compared with controls (P<0.05). The m.3635G>A mutation has resulted in decreased efficiency of ATP synthesis (P<0.05). Comparison of oxygen consumption rate showed that the basal OCR (P<0.05), ATP-linked OCR (P<0.05) and the maximum OCR (P<0.05) have all reduced to some extent compared with the controls.

CONCLUSIONThese results showed that m.3635G>A, as a LHON-associated mutation, can lead to mitochondrial dysfunction.

Adenosine Triphosphate ; genetics ; Asian Continental Ancestry Group ; genetics ; Female ; Humans ; Male ; Mitochondria ; genetics ; Mutation ; genetics ; NADH Dehydrogenase ; genetics ; Optic Atrophy, Hereditary, Leber ; genetics ; Pedigree

Objective To investigate the effects of real-time feedback devices on chest compression quality test in non-medical staff during cardiopulmonary resuscitation (CPR) training.Methods A total of 120 volunteers were recruited and trained according to American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care set in 2015.CPR performance with compression for six minutes was tested on a manikin.Volunteers were randomized into 3 groups.Group A was tested without any feedback.Group B was self-corrected in compression quality(include compression depth、rate and rebound of chest wall) using a real-time feedback device (Link CPR).Group C was guided with a metronome.All compression data were collected via WiFi signal and stored.Results Significantly better mean chest compression depth was achieved in group B than that in group A and C(5.38 ± 0.483 cm vs.4.42 ± 0.572cm and 4.25 ± 0.843 cm,P ＜ 0.05).Significantly better compression rate were observed in both group B and C than that in group A (113.4 ± 5.9 and 109.0 ± 6.8 compressions/min vs.129.6 ± 8.3 compressions/min,P ＜ 0.05).Significantly less rebounding were observed in both group B and C compared with group A (56.10 ± 32.3 and 68.30 ± 28.8 compressions vs.174.30 ± 38.8compressions,P ＜ 0.05).Pearson correlation analysis confirmed the compression rate was positively correlated with the numbers of rebounding (r=0.776,P＜0.01).Significant statistical difference in accuracy was observed among the groups (9.8％ vs.72.9％ vs.58.5％,P ＜ 0.05).Conclusions In CPR training test real-time feedback device contributes to the improvement of chest compression quality through self-adjustment of compression depth,rate and rebound.

Objective: To investigate the application value of cerebrospinal fluid circulating cell-free DNA (cfDNA) in the diagnosis and treatment of leptomeningeal metastases in non-small-cell lung cancer (NSCLC). Methods: Twenty-five patients with leptomeningeal metastases of NCSLC from Fudan University Huashan Hospital North during the period from September 2017 to November 2018 were enrolled. All 25 patients were confirmed leptomeningeal metastases by cerebrospinal fluid cytology and immunocytochemical staining of cytokeratin(CK7), carcinoembryonic antigen(CEA), thyroid transcription factor-1(TTF-1) and Ki67. The cerebrospinal fluid cfDNA was extracted and genetic variation of 12 genes including epidermal growth factor receptor(EGFR), TP53 and anaplastic lymphoma kinase(ALK) was detected by next-generation sequencing [PlasAim TM gene non-invasive detection of lung cancer (12 gene) kit, Singlera Genomics].The application value of cerebrospinal fluid cfDNA in the diagnosis and treatment of leptomeningeal metastases of NSCLC was analyzed with the cfDNA mutation data and the clinical follow-ups. Results: Morphologically typical lung cancer tumor cells with tumor immunochemistry markerCK, CK7 and CEA were found in the cerebrospinal fluid of all 25 patients. Next generation sequencing of cerebrospinal fluid showed that 96% (24/25) patients had at least one single nucleotide variation (SNV) or copy number variation (CNV). The EGFR and TP53 mutations were identified in 80% (20/25) and 48%(12/25) of the patients, respectively. In addition, patients with bone metastases had a higher rate of EGFR mutations than those without bone metastases (100% vs 64%, P<0.05). Changes in the mutant allele frequency of EGFR and TP53 in cerebrospinal fluid were consistent with patients′ disease progression parameters including neurological symptoms, imaging, and tumor biomarkers. The results indicate that genetic alteration of EGFR in cerebrospinal fluid cfDNA is an actionable biomarker for targeted therapy of leptomeningeal metastases of lung cancer. Conclusion Cerebrospinal fluid cfDNA accurately reveals the unique genetic background of leptomeningeal metastasis in NSCLC, showing great application value in the diagnosis and treatment of the leptomeningeal metastasis of NSCLC.

To investigate the clinical features and influencing factors for new-onset atrial fibrillation (AF) early after coronary artery bypass grafting. Methods    The clinical data of 339 patients undergoing coronary artery bypass grafting in our hospital from January 2012 to January 2019 were retrospectively analyzed. There were 267 males and 72 females with an average age of 37-83 (58.03±8.90) years. The clinical features and influencing factors for new-onset AF after surgery were investigated. Results    There were 234 patients of off-pump coronary artery bypass grafting (OPCABG), with 36 (15.4%) new-onset AF patients after operation, among whom 16.1% were males and 12.5% were females. There were 105 patients of on-pump coronary artery bypass grafting (CABG), with 39 (37.1%) new-onset AF patients, among whom 40.7% were males and 25.0% were females. The incidence was higher after the CABG surgery than that after the OPCABG surgery (37.1% vs. 15.4%, P<0.05). There was no statistical difference in the incidence rate between males and females (P>0.05). The incidence of new-onset AF after surgery was higher in ≥60 years patients for both  operations (18.9% and 45.8%), which was significantly higher than that in <45 years patients (P<0.05). For both operations, the incidence of new-onset AF after surgery was high on the second day (24-48 h) after surgery, and most of the AF lasted for 1 day (P<0.05). The hypertension (OR=4.983, P=0.036), frequent premature atrial contraction or atrial tachycardia (OR=17.682, P=0.002), postoperative creatine kinase isoenzyme MB (CKMB) (OR=0.152, P=0.042), left anterior and posterior diameters (OR=17.614, P<0.001) and preoperative ejection fraction (OR=7.094, P=0.011) were influencing factors for new-onset AF after OPCABG. Diabetes (OR=11.631, P=0.020), other cardiac malformations (OR=29.023, P=0.002), frequent premature ventricular contraction or ventricular tachycardia (OR=0.047, P=0.001), and postoperative CKMB (OR=3.672, P=0.040) were influencing factors for new-onset AF after CABG. Conclusion    The incidence of new-onset AF after CABG is higher than that after OPCABG, and it increases with age increasing. There is no difference in the incidence between males and females. The influencing factors for the two operations are different.